This invention relates to novel nonpeptide substituted vasopressin receptor antagonists. More particularly, the compounds of the present invention interrupt the binding of the peptide hormone vasopressin to its receptors and are therefore useful for treating conditions involving increased vascular resistance and cardiac insufficiency.
Vasopressin is a nonpeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through the vascular V-1 and renal V-2 receptor subtypes. The functions of vasopressin include contraction of uterine, bladder, and smooth muscle; stimulation of glycogen breakdown in the liver; release of corticotropin from the anterior pituitary; induction of platelet aggregation; and central nervous system modulation of behaviors and stress responses. The V-1 receptor mediates the contraction of smooth muscle, and hepatic glycogenolytic and central nervous system effects of vasopressin. The V-2 receptor, presumably found only in the kidney, effects the antidiuretic actions of vasopressin via stimulation of adenylate cyclase.
Elevated plasma vasopressin levels appear to play a role in the pathogenesis of congestive heart failure (P. A. Van Zwieten, Progr. Pharmacol. Clin. Pharmacol. 1990, 7, 49). As progress toward the treatment of congestive heart failure, nonpeptide vasopressin V-2 receptor antagonists have induced low osmolality aquaresis and decreased peripheral resistance in conscious dogs with congestive heart failure (H. Ogawa, J. Med. Chem. 1996, 39, 3547). In certain pathological states, plasma vasopressin levels may be inappropriately elevated for a given osmolality, thereby resulting in renal water retention and hyponatremia. Hyponatremia, associated with edematous conditions (cirrhosis, congestive heart failure, renal failure), can be accompanied by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Treatment of SIADH-compromised rats with a vasopressin V-2 antagonist has corrected their existing hyponatremia (G. Fujisawa, Kidney Int. 1993, 44(1), 19). Due in part to the contractile actions of vasopressin at its V-1 receptor in the vasculature, vasopressin V-1 antagonists have reduced blood pressure as a potential treatment for hypertension as well. Thus, vasopressin receptor antagonists could be useful as therapeutics in the conditions of hypertension, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, and water retention.
The present invention is directed to compounds represented by the following formula I: 
wherein
R1 is selected from xe2x80x94COOH, formyl, o-mesylate, xe2x80x94SO2OH, alkoxysulfonyl, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, xe2x80x94NR4R5, xe2x80x94OH, cyano, N-morpholino, alkoxy, aralkoxy, alkylcarbamoyl, substituted alkylcarbamoyl, alkoxycarbonyl, substituted alkoxycarbonyl, xe2x80x94NHCOR6 and xe2x80x94CONR 7R8, wherein
R4, R5, R6, and R8 are independently selected from the group consisting of H, alkyl, and aryl;
A is S, SO or SO2;
X is CH2 or carbonyl;
Z is CH2, SO2 or carbonyl, with the proviso that X is not CH2 when Z is CH2;
B is (CH2)m, NH or O;
W is aryl, substituted aryl, heteroaryl or substituted heteroaryl;
R2 is xe2x80x94N(H)YR3 or xe2x80x94YN(H)R3 wherein Y is H or carbonyl;
R3 is H, alkyl, substituted alkyl, aryl or substituted aryl;
m is 1-3;
n is 1-5; and
p is 0 or 1.
The compounds of the present invention are vasopressin receptor antagonists useful as aquaretics and, in general, in disease states of vascular resistance.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Illustrating the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
An example of the invention is a method of treating congestive heart failure in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
Another example of the invention is a method of inhibiting the onset of a condition of vascular resistance in the subject, which comprises administering to the subject a prophylactically effective dose of the pharmaceutical composition of a compound of Formula I.
Further exemplifying the invention is the method of treating congestive heart failure, wherein the therapeutically effective amount of the compound is about 1 to about 30 mg/kg/day.
Still further exemplifying the invention is the method of inhibiting the onset of congestive heart failure, wherein the prophylactically effective amount of the compound is about 1 to about 30 mg/kg/day.
An additional illustration of the invention is a method of treating a condition selected from hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. Preferably, the therapeutically effective amount of the compound administered for treating any of these conditions is about 1 to about 30 mg/kg/day.
Also included in the invention is the use of any of the compounds described above for the preparation of a medicament for treating a condition selected from inner ear disorders, hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention in a subject in need thereof.
The present invention provides nonpeptide substituted benzothiazepine compounds which are useful as antagonists of vasopressin. More particularly, the compounds of Formula I inhibit the binding of vasopressin to V-1 and V-2 receptors, and are therefore useful in treating conditions with increased vascular resistance. Examples of conditions with increased vascular resistance include, but are not limited to, congestive heart failure, edema, water retaining states, and the like. More particularly, the present invention is directed to compounds of Formula I: 
wherein
R1 is selected from xe2x80x94COOH, formyl, o-mesylate, xe2x80x94SO2OH, alkoxysulfonyl, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, xe2x80x94NR4R5, xe2x80x94OH, cyano, N-morpholino, alkoxy, aralkoxy, alkylcarbamoyl, substituted alkylcarbamoyl, alkoxycarbonyl, substituted alkoxycarbonyl, xe2x80x94NHCOR6 and xe2x80x94CONR7R8, wherein
R4, R5, R6, R7, and R8 are independently selected from the group consisting of H, alkyl, and aryl;
A is S, SO or SO2;
X is CH2 or carbonyl;
Z is CH2, SO2 or carbonyl, with the proviso that X is not CH2 when Z is CH2;
B is (CH2)m, NH or O;
W is aryl, substituted aryl, heteroaryl or substituted heteroaryl;
R2 is xe2x80x94N(H)YR3 or xe2x80x94YN(H)R3 wherein Y is H or carbonyl;
R3 is H, alkyl, substituted alkyl, aryl or substituted aryl;
m is 1-3;
n is 1-5; and
p is 0 or 1.
The nonpeptide substituted benzodiazepine compounds of the present invention are vasopressin receptor antagonists, in a preferred embodiment, the compounds are orally active. As demonstrated by the results of the pharmacological studies described hereinafter, the compounds show the ability to block vasopressin binding to recombinant V-1 and V-2, and therefore are useful as therapeutics in or prophylactics against the conditions of hypertension, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, and water retention.
In particular, compounds of Formula I, wherein R1 is xe2x80x94COOH, formyl, o-mesylate, xe2x80x94SO2OH, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, cyano, N-morpholino, alkoxy, aralkoxy, alkylcarbamoyl, or substituted alkylcarbamoyl, are embodiments of the present invention.
More particularly, compounds of Formula I wherein A is S, p is 0, and n is 1 or 2 are embodiments of this invention.
Compounds of Formula I wherein X is CH2 and Z is carbonyl, are also particular embodiments of this invention.
Compounds of Formula I wherein W is phenyl, substituted phenyl, benzyl, substituted benzyl, pyridinyl, substituted pyridinyl, naphthyl or substituted naphthyl, are still particular embodiments of this invention.
Compounds of Formula I, wherein R2 is xe2x80x94N(H)YR3 in which Y is carbonyl and R3 is substituted phenyl, are further particular embodiments of the present invention. In particular, compounds of Formula I wherein R2 is xe2x80x94NHCO(2-Ph)Ph are yet other embodiments of the present invention.
Compounds of Formula I, wherein R3 is phenyl or substituted phenyl, are still other embodiments of the present invention.
In addition, compounds of Formula I, wherein R1 is amine, substituted amine, xe2x80x94NHCOR6 or xe2x80x94CONR7R8 wherein R61, R7 and R8 are as described hereinabove, are particular embodiments of the present invention.
More particularly, compounds of Formula I wherein
R1 is selected from xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94NHBOC, xe2x80x94N(BOC;)2, xe2x80x94NHCOC (CH3)2NH2, xe2x80x94N(COC (CH3)2NH2)2 and xe2x80x94NCH2 (2,5xe2x80x94OCH3) Ph;
W is Ph or substituted Ph;
R2 is xe2x80x94NH2, xe2x80x94NHAc, xe2x80x94NHCO(2-CH3)Ph or xe2x80x94NHCO(2-Ph)Ph; and
p is 0
are also particular embodiments of the present invention.
Compounds of Formula I wherein R1 is xe2x80x94OH are particular embodiments of the present invention, too.
More particularly, compounds of Formula I wherein
R1 is xe2x80x94OH;
W is heteroaryl, Ph or substituted Ph;
R2 is xe2x80x94NH2, xe2x80x94NHAc, xe2x80x94NHCOCH3, xe2x80x94NHCO(2-CH3)Ph, xe2x80x94NHCO(2-Ph)Ph, xe2x80x94NHCO(2-CH3,5-F)Ph, or xe2x80x94NHCO(3,4-Cl)Ph; and
p is 0
are also particular embodiments of the present invention.
Compounds of Formula I wherein R1 is alkoxycarbonyl, substituted alkoxycarbonyl, or xe2x80x94CONR7R8 wherein R7 and R8 are as described hereinabove, are particular embodiments of the present invention as well.
More particularly, compounds of Formula I wherein
R1 is alkoxycarbonyl, substituted alkoxycarbonyl, or xe2x80x94CONR7R8 wherein R7 and R8 are as described hereinabove;
Z is carbonyl;
W is Ph or substituted Ph;
R2 is xe2x80x94NHCO(2-Ph)Ph; and
p is 0
are also particular embodiments of the present invention.
The following compounds are further particular embodiments of the present invention:
Compound 24: 2-Carboxymethyl-1-oxo-5-(4-(2-phenylbenzoylamino)benzoyl)-1,5-benzothiazepine 
Compound 29: 2-Carboxymethyl-5-(4-(2-phenylbenzolylamino)benzoyl)-1,5-benzothiazepine 
Compound 31: 2-(2-Carboxyethyl)-5-[4-(2-phenylbenzoylamino)benzoyl]-1,5-benzothiazepine 
Compound 33 and Compound 34: 2-Carboxymethyl-5-[4-(2-phenylbenzoylamino)benzoyl]-1, 5-benzothiazepine 
The compounds of the present invention may also be present in the form of a pharmaceutically acceptable salt or salts. For use in medicine, the salt or salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salt or salts.xe2x80x9d Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. Representative basic/cationic salts include, but are not limited to, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc.
Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
As used herein, xe2x80x9ctreatingxe2x80x9d a disorder means eliminating or otherwise ameliorating the cause and/or effects thereof. To xe2x80x9cinhibitxe2x80x9d or xe2x80x9cinhibitingxe2x80x9d the onset of a disorder means preventing, delaying or reducing the likelihood of such onset.
Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. The term xe2x80x9cprophylactically effective amountxe2x80x9d refers to that amount of active compound or pharmaceutical agent that inhibits in a subject the onset of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician, the delaying of which disorder is mediated by the reduction of increased vascular resistance.
Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
Unless otherwise noted, xe2x80x9calkylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d as used herein, whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Cycloalkyl groups contain 3 to 8 ring carbons and preferably 5 to 7 rung carbons.
The term xe2x80x9cArxe2x80x9d or xe2x80x9carylxe2x80x9d as used herein, whether used alone or as part of a substituent group, refers to an aromatic group such as phenyl and naphthyl. When the Ar or aryl group is substituted, it may have one to three substituents which are independently selected from C1-C8 alkyl, C1-C8 alkoxy, fluorinated C1-C8 alkyl (e.g., trifluoromethyl), fluorinated C1-C8 alkoxy (e.g., trifluoromethoxy), halogen, cyano, hydroxy, amino, nitro, C1-C4 alkylamino (i.e., xe2x80x94NHxe2x80x94C1-C4 alkyl), C1-C4 dialkylamino (i.e., xe2x80x94Nxe2x80x94[C1-C4 alkyl]2 wherein the alkyl groups can be the same or different), or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from C1-C8 alkyl, C1-C8 alkoxy, fluorinated C1-C8 alkyl, fluorinated C1-C8 alkoxy, halogen, cyano, hydroxy, amino, nitro, alkylamino, dialkylamino or heteroaryl. xe2x80x9cPhxe2x80x9d or xe2x80x9cPHxe2x80x9d denotes phenyl.
The term xe2x80x9cheteroarylxe2x80x9d as used herein represents a stable five or six membered monocyclic aromatic ring system which consists of carbon atoms and from one to three heteroatoms selected from N, O or S. The heteroaryl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl or quinolinyl. Prefered heteroaryl groups include pyridinyl, thiophenyl, furanyl and quinolinyl. When the heteroaryl group is substituted, the heteroaryl group may have one to three substituents which are independently selected from C1-C8 alkyl, halogen, aryl, heteroaryl, alkoxy, alkylamino, dialkylamino, arylamino, nitro, and hydroxy.
The term xe2x80x9caralkoxyxe2x80x9d indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy).
The term xe2x80x9cacylxe2x80x9d as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group.
The term xe2x80x9chalogenxe2x80x9d shall include iodine, bromine, chlorine and fluorine.
The terms xe2x80x9csubstituted alkylcarboxy,xe2x80x9d xe2x80x9csubstituted aralcarboxyxe2x80x9d and xe2x80x9csubstituted alkylcarbamoylxe2x80x9d denote alkylcarboxy, aralcarboxy and alkylcarbamoyl substituted with radicals including, but not limited to, halogen, alkyl, alkoxy, amino, and the like.
Whenever the term xe2x80x9calkylxe2x80x9d, xe2x80x9cacylxe2x80x9d, or xe2x80x9carylxe2x80x9d or either of their prefix roots appear in a name of a substituent (e.g., aralkyl, dialkylamino) it shall be interpreted as including those limitations given above for xe2x80x9calkylxe2x80x9d, xe2x80x9cacylxe2x80x9d, and xe2x80x9caryl.xe2x80x9d Designated numbers of carbon atoms (e.g., C1-C6) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The utility of the compounds to treat disorders of increased vascular resistance can be determined according to the procedures described herein. The present invention therefore provides a method of treating vascular resistance disorders in a subject in need thereof which comprises administering any of the compounds as defined herein in a quantity effective to treat vascular resistance disorders. The compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral.
The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
To prepare the pharmaceutical compositions of this invention, one or more compounds of Formula I or salt thereof of the invention as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 1 mg to 30 mg/kg and may be given at a dosage of from about 1 to 30 mg/kg/day (preferred 3 to 15 mg/kg/day). The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a stereogenic HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.